rs72646861

Variant names:

• chr2-178584459-G-A
• rs72646861
• NM_001267550.2:c.65092C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178584459-G-A
• chr2-178584459-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.65092C>T​(p.Arg21698Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00438 in 1,613,262 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21698L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (105 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: 5.15
• Publications: 12 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006336987).
• BP6: Variant 2-178584459-G-A is Benign according to our data. Variant chr2-178584459-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00351 (534/152130) while in subpopulation SAS AF = 0.0342 (165/4828). AF 95% confidence interval is 0.0299. There are 4 homozygotes in GnomAd4. There are 302 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.65092C>T	p.Arg21698Cys	missense	Exon 311 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.60169C>T	p.Arg20057Cys	missense	Exon 261 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.57388C>T	p.Arg19130Cys	missense	Exon 260 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.65092C>T	p.Arg21698Cys	missense	Exon 311 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.64936C>T	p.Arg21646Cys	missense	Exon 309 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.64816C>T	p.Arg21606Cys	missense	Exon 309 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 530 AN: 152012 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.0341

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00827 AC: 2054 AN: 248328 AF XY: 0.00978

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.0201

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00262

Gnomad OTH exome AF: 0.00714

GnomAD4 exome AF: 0.00447 AC: 6528 AN: 1461132 Hom.: 105 Cov.: 32 AF XY: 0.00550 AC XY: 3996 AN XY: 726854

African (AFR) AF: 0.000598 AC: 20 AN: 33444

American (AMR) AF: 0.00174 AC: 78 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0198 AC: 518 AN: 26120

East Asian (EAS) AF: 0.0151 AC: 597 AN: 39566

South Asian (SAS) AF: 0.0352 AC: 3040 AN: 86244

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53392

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5762

European-Non Finnish (NFE) AF: 0.00160 AC: 1783 AN: 1111558

Other (OTH) AF: 0.00643 AC: 388 AN: 60344

GnomAD4 genome AF: 0.00351 AC: 534 AN: 152130 Hom.: 4 Cov.: 32 AF XY: 0.00406 AC XY: 302 AN XY: 74370

African (AFR) AF: 0.000457 AC: 19 AN: 41532

American (AMR) AF: 0.00144 AC: 22 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 64 AN: 3468

East Asian (EAS) AF: 0.0199 AC: 102 AN: 5136

South Asian (SAS) AF: 0.0342 AC: 165 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00205 AC: 139 AN: 67966

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00366 Hom.: 20

Bravo AF: 0.00285

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00279 AC: 23

ExAC AF: 0.00879 AC: 1062

Asia WGS AF: 0.0350 AC: 122 AN: 3476

EpiCase AF: 0.00218

EpiControl AF: 0.00373

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	6	not provided (6)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.90
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.36
Sift	Benign	0.053	T
Polyphen		1.0	D
Vest4		0.50
MVP		0.61
MPC		0.52
ClinPred		0.048	T
GERP RS		6.1
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72646861; hg19: chr2-179449186;